Water-soluble fractions of Phlebodium decumanum and its use as nutritional supplement in AIDS and cancer patients

ABSTRACT

A purified and standardized water-soluble fraction, prepared from the leaves of a variety of  Phlebodium decumanum  and identified as EXPLY-37, is adequate for the manufacturing of formulations, useful as nutritional supplements of general application, and more particularly, in patients suffering from general weakness and cachexia, such as AIDS an cancer patients. The formulations can contain, optionally, powdered  Phlebodium decumanum  rhizome and/or  Phlebodium decumanum  rhizome extract, together with the appropriate excipients for preparing said formulation as powders, capsules and syrups.

FIELD OF THE INVENTION

This invention relates to a purified and standardized water-solublefraction obtained from the leaves of a cultivated variety of Phlebodiumdecumanum, identified as EXPLY-37, to formulations containing it and totheir use as nutritional supplements of general application andparticularly, in patients suffering from general weakness and cachecticsyndrome, as AIDS and cancer patients. Such formulations can also beused in combination with anti-retroviral drugs in AIDS patients and withconventional anticancer treatments (surgery and/or radio-andchemotherapy) in order to improve the efficacy and to reduce theundesired effects of such treatments. The formulations are also usefulin the recovery of patients under those treatments.

BACKGROUND OF THE INVENTION

Cachexia is a complex syndrome characterized by appetite and body weightloss, general weakness, anemia and asthenia. This syndrome is associatedto a metabolic dysbalance and shown by weight loss and generalizedwasting: the organism is unable to maintain the adequate energy supplyand spends its own lipid store and muscle protein.

It is accepted that a high percentage (50-90%) of HIV infected patientssuffer from some kind of malnutrition. This disturbance can beattributed to alterations in the intake, absorption and metabolism offoods [C. Fields-Gardner, Nutr.Clin. Pract. 1995, 10(5), 167-176.]Severe weight loss is closely related to the mortality increase in AIDSpatients. It may be related, on the other hand, to some kind ofgastrointestinal pathology, anorexia, systemic infections and can appearin patients with advanced disease and CD4+ count lower than 100 [D. P.Kotler, AIDS Res. Hum. Retroviruses 1994, 10(8), 930-934]

Wasting syndrome associated to HIV infection is characterized byprogressive weight loss and increasing weakness, frequently associatedto fever and diarrhea. The causes of these alterations are complexes,multifactorial and seem to be related to inadequate diets, malabsorptionphenomena, metabolic dysbalance and activity of some cytokines such astumor necrosis factor (TNF), IL-1, IL-6 and α-IFN [S. E. Weinroth et al.Infect. Agents Dis. 1995, 4,76-94]. P. Kelly et al. [Q.S. Med. 1996, 89(II), 831-837] found a relationship between the severity of cachexia ina group of African males and the high cytokine activity, specially highconcentrations of sTNF55, although no correlation could be establishedwith either oesophagic candidiasis or any intestinal opportunisticinfection.

The relationship between wasting syndrome and low blood levels oftestosterone has been demonstrated in male AIDS patients. Special diets,testosterone, nandrolone [J. Gold et al. 1996, 10 (7), 108-112] andgrowth hormone [M. Shambelan et al. Ann. Inter. Med. 1996, 125 (11),873-882] have been used for the treatment of cachexia in AIDS patients.

The relationships between nutrition, HIV infection and immune system [J.M. Hoyt et al., II. Assoc. Nurses AIDS care 1991, 2 (3), 16-28,] and therole of certain cytokines in the wasting syndrome in AIDS patients, canbe considered as the basis for new treatments involving the use ofimmunomodulators. The use of thalidomide, an immunomodulating drug, inthe treatment of the wasting syndrome associated to AIDS has recentlybeen published [G. Reyes-Teran et al., AIDS, 1996, 10, 1501-1507].

On the other hand, cachexia is also associated to the high mortalityrate in cancer patients, this rate being estimated by some authors as30-70%. Many cancer patients die after continuous weight loss andgeneralized weakness. Oncology patients with associated cachexia have anegative prognostic as the possibilities of effective chemoterapeutictreatments are substantially reduced. Consequently, an effectivetreatment of cachexia should improve the general condition of thepatient: more effective chemotherapy, better quality of life and morefavorable prognosis of the disease could be achieved.

However, all the approaches for slowing down or reverting cachexia havebeen focused on the improvement of nutritional supply through specialdiets and regimen without positive results.

Recent publications are now stressing the relationships between the highlevels of certain pro-inflammatory citokynes and cancer cachexia: TNFα,IL-1, IL-6 and IFN gamma [P. Elliot et al., Drug &. Market Development1989, 9, 26-18.] This dysfunction of the immune system, together withreduction in the NK cell activity and plasma levels of cystine andglutamine, accompanied of urea overproduction, shown in differentpathologies, is extremely important in the induction and progression ofcachexia in cancer patients. Although the induction mechanism by suchcytokines is unknown, antagonizing their effects by usinginmunomodulators is one of the most updated approaches to revertcachexia.

It is obviously necessary to develop new ways to stop or revert thecachetic syndrome in order to improve the quality of life and to enhancethe efficacy of basic treatments.

The fern known for years as Polypodium leucotomos has historically beenused by the Honduran natives, as infusions of leaves and rhizomes, forthe treatment of malign tumors, rheumatoid arthritis and psoriasis.Horvath et al. [Nature, 1967, 214, 1256-1258] showed both the in vitroand in vivo antitumor effect of an aqueous extract of the fern. Later, awater soluble fraction from the leaves of Polypodium leucotomos has beenwidely studied. Its inmunomodulator/inmunosuppresor profile and itsantioxidant and anti-free radical properties have been described [M. D.Fernandez & al. 1^(st) World Congress on Medicinal and Aromatic Plantfor Human Welfare, Maastricht, 1992; J. Rayward et al., 2^(nd)International Congress on Biological Response Modifiers, San Diego, USA,S. Gonzalez & al., Photodermatol, Photoimmunol, Photomed, 1996, 12,45]

The use of extracts from the genus Polypodium, and more specificallyfrom Polypodium leucotomos, as antioxidants and photoprotectants hasbeen claimed in the patent PCT/US 96/01808 by Pathak et al. (1996).

The present invention provides a water soluble fraction obtained fromthe leaves of a cultivated variety of Phlebodium decumanum, purified andstandardized, identified as EXPLY-37, its production and its use in themanufacturing of formulations useful as nutritional supplements. Theplant material from which the water soluble extract employed herein,identified as “EXPLY 37”, is obtained from the leaves of a cultivatedvariety of Phlebodium decumanum found in the Yojoa Lake region ofnorthern Honduras. In accordance with the provisions of 37 C.F.R. 1.802this plant material has been deposited in an International DepositaryAuthority (IDA) established under the Budapest Treaty on theInternational Recognition of the Deposit of Microorganisms for thePurposes of Patent Procedure. This deposit was made by transmission of anumber of spores of the variety of Phlebodium decumanum from which EXPLY37 is extracted on Oct. 19, 2000 to the National Collection ofIndustrial and Marine Bacterial Ltd. (NCIMB), Aberdeen, Scotland (UnitedKingdom). The deposit was received on Oct. 16, 2000.

DESCRIPTION OF THE INVENTION

This invention is addressed, but not limited, to the manufacturing of awater-soluble fraction from the leaves of a cultivated variety ofPhlebodium decumanum, purified and standardized, identified as EXPLY-37,to the preparation of EXPLY-37 formulations and to the use of theseformulations as nutritional supplements in AIDS and cancer patients. Theformulations can be used together with anti-retroviral drugs in AIDSpatients and associated to conventional oncology treatments (surgeryand/or radio-and chemotherapy), in order to improve the efficacy andreduce the side effects in the recovery of patients under thosetreatments.

1. Phlebodium decumanum

This Polypodiacee, belonging to the Subgenus Phlebodium, within theGenus Polypodium, is organically cultivated and processed in thefacility near the Yojoa lake (Northern Honduras). This facility is ownedby HELSINT S.A.L. (Spain) and exploited by Helechos International,Honduras, S.A. (HIH). The plant has been considered for years asPolypodium leucotomos but has been reclassified in 1992, according tothe in situ studies carried out by Prof.Cirile Nelson, Director of theHerbario TEFH, Department of Biology, UNAH (Tegucigalpa, Honduras),Prof. Sinn Sandberg, Uppsala University, and Prof. Antonio Molina, fromthe Paul C. Stanley Herbario and the Escuela Agricola Panamericana. Afull agreement has been reached on the new nomenclature. Therelationships among the different Polypodium species have beenfurthermore reviewed by M. Väsange, Ph. Thesis, Uppsala University,1996.

The lake Yojoa cultures are the only ones existing in the world whereboth ferns—Phlebodium decumanum and Polipodium leucotomos—, arecultivated.

2. Water-soluble Fractions of Phlebodium decumanum

EXPLY-37 is the tradename, property of HELSINT S.A.L. and applied to theExtract of Phlebodium decumanum from the Yojoa Lake. No 37 correspondsto the extraction method selected among those tested for the preparationof the extract from the leaves and is based on the methods disclosed inpatents G B 2,024. 622 A, GB 2075,834-A, ES 8902092 and more recently inWO 96/5139.

Sporulated leaves from Phlebodium decumanum, dried and ground, aredelipidated by treatment with petroleum ether, methylene choride ormixtures petroleum ether/methylene chloride, then extracted with amixture of methanol/water. An alternative method consists in theextraction with a mixture of methyl alcohol/water followed bydelipidation of the extract with petroleum ether, methylene chloride ormixtures petroleum ether/methylene chloride.

By removing the methyl alcohol at reduced pressure the remainingwater-soluble fraction is purified by passing it through a mixedion-exchange column, treatment with active charcoal, sodiummetabisulphyte and filtration.

The purified water-soluble fraction is concentrated until abatch-to-batch constant and reproducible composition within a narrowrange. Example 1 describes a method for the preparation of awater-soluble fraction from the leaves of Phlebodium decumanumidentified as EXPLY-37. A typical composition of EXPLY-37 is shown inTable 1.

The tradename EXPLY-37 has been applied by HELSINT S:A:L to distinguishthe extract from the variety of Phlebodium decumanum cultivated in thelake Yojoa facility and to differentiate it from wild varieties ofPhlebodium decumanum from other origins.

A water-soluble fraction, purified and standardized, can also beobtained from the rhizome by the following method: the rhizome, afterremoving all the villosities, is washed with an sterilizing solution anddeionized water, dried, ground, and extracted with a mixture of methylalcohol/water. After removal of the alcohol in the vacuum, the cloudywater-soluble fraction is treated with petroleum ether, methylenechloride or mixtures petroleum ether/methylene chloride to remove theremain lipids. The solution is clarified with active charcoal, treatedwith sodium metabisulphite, filtered and concentrated until abatch-to-batch constant and reproducible composition, within a narrowrange. Example 2 describes a method for the preparation of awater-soluble fraction, or extract, from the rhizome of Phlebodiumdecumanum. A typical composition of such fraction is shown on TABLE 2.

3. Formulations Containing EXPLY-37 for Use by Oral Route

The invention provides formulations containing EXPLY-37 useful asnutritional supplements. These formulations may additionally containrhizome and/or rhizome water-soluble fraction. The formulations,adequate for oral administration, can be solid or liquid and used aspowders, soft or hard gelatine capsules or syrups.

3.1 Solid Formulations Containing EXPLY-37 3.1.a) Mixture ContainingPowdered Rhizome of Phlebodiun decumanum and EXPLY-37

This preparation can be obtained by a method consisting of the followingsteps:

successive washings of the rhizome with water containing activechlorine, de-ionized water, ethyl alcohol and de-ionized water.

drying of the rhizome

grinding of the rhizome and homegenization to a selected particle size

incorporation of EXPLY-37

drying.

This mixture of EXPLY-37 and Phlebodium decumanum rhizome, ground andhomogenized, can be used as a powder to fill hard gelatine capsulescontaining between 100 and 500 mg powder. The ratio [ground andhomogenized rhizome: EXPLY-37] in the mixture is within the range 4:1 to1.1.

3.1.b) Mixture Containing Powdered Phlebodium decumanum RhizomesEXPLY-37 and Phlebodium decumanum Rhizome Extract

This preparation can be obtained by a similar method to that summarisedin 3.1.a), although different mixtures of EXPLY-37 and rhizome extract(50:50 to 95:5) can be added in different proportions. The solid mixturecontaining EXPLY-37, rhizome powder and rhizome extract of Phlebodiumdecumanum, prepared as a dry powder, can be used to fill hard gelatinecapsules containing 100-500 mg solid powder. The relative proportions[EXPLY-37+rhizome extract]:[rhizome] can be in the range 4:1 to 1:1

3.2 Liquid Formulations Containing EXPLY-37

These formulations can be prepared as soft gelatine capsules and syrups.

3.2.a) Soft gelatine capsules containing EXPLY-37

The capsules con be filled by direct injection of diluted EXPLY-37having the adequate viscosity. These capsules can contain 50-700 mgEXPLY-37.

3.2.b) Soft gelatine capsules containing EXPLY-37 and Phlebodiumdecumanum rhizome extract.

These capsules can be obtained by the following process:

Preparation of a homogeneous mixture containing EXPLY-37 and rhizomeextract, the relative proportions ranging within the range (50:50 to95:5)

Dilution of the mixture and injection in soft gelatine capsules. Totalcontent [EXPLY-37+rhizome extract]: 50 to 750 mg.

3.2.c) Syrups containing EXPLY-37

A syrup can be prepared by homogenizing EXPLY-37 with the followingcomponents:

Saccharum officinarum liquid extract

Glycyrrhiza glabra liquid extract

Citric acid

Preferred formulations are those containing EXPLY-37 at a concentrationof 50-500 mg/g.

3.2.d) Syrups containing mixtures of EXPLY-37+Phlebodium decumanumrhizome extract [relative proportions (50:50) to (95:1)] and thefollowing components:

Sacharum officinarum liquid extract

Glycirrhiza glabra liquid extract

Citric acid

Preferred formulations are those containing the mixture[EXPLY-37+rhizome extract] at a concentration of 50-500 mg/g.

3.2.e) Syrups containing EXPLY-37.

A different syrup can be prepared by the incorporation of EXPLY-37 to anaqueous solution containing the following excipients:

invert sugar

sorbitol

propylenglycol

Preferred formulations are those containing EXPLY-37 at a concentrationof 20-500 mg/ml.

3.2.f) Syrups containing EXPLY-37 and Phlebodium decumanum rhizomeextract.

Syrups can be prepared by incorporating a mixture containing variousproportions [EXPLY-37: rhizome extract (50:50) to (95:5)] into anaqueous solution of following excipients:

invert sugar

sorbitol

propylenglycol

Preferred formulations are those containing 20-50 mg [EXPLY-37+rhizomeextract/ml]

EXPLY-37 formulations provided in this invention are useful asnutritional supplement of general use.

These formulations are, particularly adequate for the treatment ofmalnutrition, body weight loss, generalized wasting and cachecticsyndrome in AIDS patients [see the results obtained with AIDS patients:Clinical Results. I. AIDS patients with advanced HIV infection] and as asupplement to treatments with anti-retroviral drugs. The formulationsare also useful for the treatment of cancer patients showing generalizedweakness and cachectic impairment: as cachexia is slowing-down andreverting, a general improvement is obtained allowing a more efficaciousapplication of the appropriate anti-cancer treatments. EXPLY-37formulations can also be used as adjuvant in conventional oncologytreatments (surgery and/or radio- and chemotherapy) and for the recoveryof cancer patients, previously under such treatments [see the resultsobtained in cancer patients: Clinical Results. II. Treatment of cancerpatients].

Treatment of cachectic syndrome in patients with advanced HIV infectionis better performed by administration of the formulations provided inthis invention at daily doses comprised between 1 and 5 g, expressed asEXPLY-37. Similar doses are adequate for the treatment of cachecticsyndrome in cancer patients, as adjuvant in conventional anti-cancertreatments and in the recovery of cancer patients following to thosetreatments.

The following examples illustrate well the invention although they mustnot be considered limiting of the same.

EXAMPLE 1 Preparation of EXPLY-37 from Phlebodium decumanum Leaves

Sporulated, freshly, harvested leaves from Phlebodium decumanum aredried for 1 week in a drying room by introducing pressed air at 40-50°C. Once dried, the leaves are ground. A mixture of small particles andfine powder is obtained. 100 kg dry, ground leaves are extracted 3 timeswith 400 litters of 7/3 methyl alcohol/de-ionized water at 40° C. for 12hours. Hydromethanolic extracts are collected and concentrated at 40° C.under reduced pressure until complete removal of the alcohol. The finesuspension obtained is treated 3 times with an equal volume of non-polarsolvent, preferently petroleum ether or petroleum ether/dichoro.methanemixtures, in order to remove any residual lipids. The delipidated watersoluble fraction is purified by passing it through an ion-exchange resincolumn followed by treatment with active charcoal, sodium metabisulfiteand filtration. Concentration of the solution under reduced pressure,until a final water content of 20%, yields 5-10% (5-10 kg) of EXPLY-37.

TABLE 1 Composition of the purified, standardized water-soluble fractionfrom Phlebodium decumanum leaves (EXPLY-37). % Total solid content79.5-81.5 Ash 10-12 Total N 0.7-0.9 Total protein 4.9-5.9 Lipids <0.2Carbohydrates 60.5-64.5 pH   5-5.1 Refractive index 1.4-1.5 UVabsorption   235-237 nm   274-284 nm Absorbance at 290 nm 2.5-5  

EXAMPLE 2 Preparation of Extracts from Phlebodium decumanum Rhizome

100 kg wet rhizomes, freshly harvested are successively extracted at 40°C., for 10 hours with:

a) 400 L methylalcohol

b) 400 L methylalcohol/water (8:2)

c) 400 L methylalcohol/water (7:3)

The different extracts are combined and concentrated at 40° C. and 25 mmuntil complete removal of the alcohol. The cloudy aqueous solution isextracted twice with methylene chloride or mixtures methylenechloride:petroleum ether.

The aqueous phase is then treated with active charcoal until a finalabsorbance of 0.5-1.5 at 290 nm is reached. Final concentration of thesolution at 40° C. and 25 mm pressure gives a water-soluble fractionwith a total solid content of 80%. A yield of 1-3 kg of purified andstandardized rhizome extract is obtained. Its composition is batch tobath constant and reproducible within narrow limits (Table 2).

TABLE 2 Composition of the purifieds standardized water-soluble fractionfrom Phlebodium decumanum rhizomes % Total solid content 80-81 Ash 10-12Total N 0.6-0.7 Total protein   4-4.5 Lipids 0.5 Carbohydrates 65-66 pH  5-5.1 Refractive index 1.4-1.5 UV absorption peaks at 237 nm and 272nm Absorbance at 290 nm 0.5-1.5

EXAMPLE 3 Capsules Containing EXPLY-37 and Rhizome

50 kg fresh rhizomes from Phebodium decumanum, freed from villosities,are washed by successive immersions in a dilute aqueous solutioncontaining active chlorine, de-ionized water, absolute ethyl alcohol andsterile de-ionized water. The rhizomes are dried in a fluid layer dryerat 40°-50° C. for 2 hours. The dry rhizomes are ground and sieved. Afine powder is obtained.

7,5 Kg EXPLY-37 are added to 22.5 kg rhizome powder with stirring in a100 L capacity stainless steel mixer. Stirring continues until ahomogeneous mixture is obtained. The mixture is then dried on plates inthe oven at 40-50° C. for 24 hours. The powder is sieved through a 18mesh sieve. Capsules containing 300 mg powder are prepared.

EXAMPLE 4 Capsules Containing EXPLY-37 Enriched Powder

By following a process similar to that described in Example 3, themixture is prepared with 25.5 Kg rhizome powder and 18.5 Kg EXPLY-37.After drying homogenizing and sieving, capsules containing 440 mg powderare prepared.

EXAMPLE 5 Capsulas Containing EXPLY-37, Rhizome and Rhizome Extract

By following a similar process to that described in Example 3, a finalmixture containing 26.8 kg powdered dry rhizome, 10 kg EXPLY-37 and 3.2kg rhizome extract is prepared. Capsules containing 400 mg dry powderare manufactured. The relative proportions [XPLY-37: rhizome extract]can vary within a wide range (50:50) to (95:5)

EXAMPLE 6 EXPLY-37 Syrup

A homogeneous mixture is made up of 7.8 kg of Saccharum officinarumliquid extract and 190 g glycyrrhiza glabra liquid extract by stirringin a stainless steel mixer tank provided of a paddle stirring element at20 rpm. 10 g citric acid are then added, followed by 2 kg EXPLY-37.Stirring is continued at 37° C. until complete homogenization. A syrupcontaining 200 mg EXPLY-37 /g is obtained.

By using different amounts of EXPLY-37 and making the necessarycorrections in the amounts of excipients, syrups containing 50-500 mgEXPLY-37/g are prepared.

EXAMPLE 7 Syrups Containing EXPLY-37 and Rhizome Extract

By following the steps described in Example 6, a syrup containing 1 kgEXPLY-37+1 kg rhizome extract is obtained. Final concentration: 200 mgwhole extract/g.

Syrup having a composition in the range 50-500 mg total extract/g can beprepared in a similar way. The relative proportions [EXPLY-37: rhizomeextract ] can vary from (50:50) to (95:5)

EXAMPLE 8 Syrups Containing EXPLY-37 and Rhizome Extract

5,000 g invert sugar, 2,500 g sorbitol and 50 g propylenglycol aresuccessively added on 2,450 mL de-ionized water in a glass tank providedof anchor stirring element. When the mixture is fully homogenized, 2.5Kg EXPLY-37 or 2 Kg EXPLY-37 and 0.5 Kg rhizome extract are added underslow stirring at temperature of 30°-40° C. Syrup concentration: 200mg/ml, expressed as EXPLY-37 or EXPLY-37+rhizome extract].

Clinical Results I. Patients with Advanced HIV Infection

The number of HIV infected patients is reaching dramatic levels inCentral America and Caribbean countries. Honduras' case is known by thenumber of patients in advanced stager of the disease, the early age ofmany of these patients and the lack of resources for diagnosis,prevention and treatment of the disease with anti-retroviral drugs.

Honduran patients, knowing the existence of the lake Yojoa Polypodiaceecultures, requested some compassionate remedies for the improvement oftheir general condition. HIH decided to prepare different formulationsto be supplied as nutritional and energetic supplements to thosepatients willing to use the remedy. Said formulations are within thescope of this patent application.

1. Dose exploration in individual patients

Preliminary results correspond to five advanced patients in verydeteriorated conditions. No inclusion criteria were applied. Thesepatients were given, together with the regular diet, EXPLY-37 syrupcontaining only EXPLY-37 and prepared as in Example 8. Daily doses weregiven thrice daily and ranged between 1 and 3 g/day. After the firstmonth of treatment all five patients received 3 g/day. Results aresummarised in table 3

TABLE 3 Results in isolated cases Months of Body weight Patient Age/sexAppetite treatment Quality of life 1 52/M 5+ 9 Body weight increase tonormal figures. Professional activity became to normal at the 2^(nd)month 2 21/F 4+ 5 Body weight increase to normal figures. Quality oflife 3 22/M 4+ 5 Body weight increase to normal figures. Quality of life4 27/M 3+ 4 60% body-weight increase. Professional activity became tonormal at the 1^(st) month of treatment  5* 20/M — — *This patient diedtwo days after initiating the treatment. Appetite scale 1+ to 5+.

2. Groups of controlled patients

A first group of 5 patients was treated according to a simple protocolincluding the following criteria:

Age 18-35 years

Number of patients 10, both sexes

Inclusion criteria

Advanced HIV infection

Absence of opportunistic infection

No treatment with anti-retroviral drugs

CD4++ not lower than 400

Body weight loss in the previous 6-month period not lower than 10%

Parameters to be measured

Appetite recovery

Body weight evolution

Quality of life

This group of patients is on the 2^(nd) month of treatment. They arereceiving as a nutritional supplement 3.1 g EXPLY-37 doses par day as asyrup prepared according to Example 8. Table 4 summarizer the resultscorresponding to the first 5 controlled patients.

TABLE 4 Results in groups of controlled patients Months of Body weightQuality Patient Age/sex Appetite treatment of life 1 32/M 3+ 2Progressive body weight gain. Improvement in the quality of life 2 33/F3+ 2 Id 3 26/F 3+ 2 Id 4 27/M 4+ 2 Id 5 33/F 3+ 2 Id

The initial inclusion criteria were modified from patient no 6 on due tothe difficulties in selecting patients with CD4+ count not lower than400: most of the examined patients showed a CD4+ count between 100 and200 and were suffering from different associated opportunisticinfections.

A second group of patients meeting the new inclusion criteria are beingtreated with capsules containing [EXPLY-37 +rhizome] and prepared as inExample 4. The daily dose is 6-12 capsules/day. The first 4 patientsshowed a general improvement similar to that observed in the previousgroups: rapid appetite gain, smooth and progressive body-weight gain,improvement in the quality of life and resumption of both personal andprofessional activities in those cases where these activities had beendiscontinued.

II. Treatment of Cancer Patients

Continuous use of different EXPLY-37 formulations in cancer patientswith different type of tumors at different stages, either duringconventional anticancer treatments or following to the application ofsuch treatments has shown the efficacy of said formulations in:

reversion of cachexia and quality of life recovery in very ill patients.

application of new chemotherapy protocols in recovered patients.

maintenance of good general condition and quality of life in saidpatients.

reduction of the undesirable effects in patients under chemotherapy.

general condition and quality of life recovery following to theapplication of conventional anticancer treatments.

Experience has been accumulated for several years after the positiveresults obtained with the first patient.

Table 5 summarizes some representative cases where a relationshipbetween the positive evolution in the patient condition is associated tothe continuous use of EXPLY-37.

Results Patient Sex/Age Pathology/date Treatment EXPLY-37 5/98 1 M/60Colon neoplasia /1/94 Surgery 1-3 g/day starting 01/94. Excellenttolerance to Chemotherapy in 1994 Alternatively formulationschemotherapy. Body examples 5, 6, 7, 8 weight gain. Excellent quality oflife 2 M/58 Colon neoplasia /02/97 Surgery 2 g/day starting 2/97Progressive recovery of Chemotherapy Formulations as in example qualityof life. Resuming 6 the sport activity (hobby) 5/98 3 F/49 Breastcarcinoma II 10/93 Total mastectomia 2 g/day starting 9/97. Goodtolerance to (CT) Liver metastasis 10/95 Surgery Formulations example 4ad Good quality of life Bone metastasis 9/97 Chemotherapy (under 5Favorable evolution of way) metastasis 4 F/51 Breast carcinoma and liverTotal mastectomia 1-2 g/day starting 01/97. Body weight back tometastasis /7/95 Chemotherapy cycles in Formulations as in examplenormal figures. 1996 6 Excellent quality of life. Metastasis inregression. 5 M/52 Bladler neoplasia III 10/95 Transuretral resection1-2/day starting 10/96. Very surprising and Mytomycin C instillations,Formulations as in 4, 6, 7, favorable evolution in radiotherapy, BCG1997. (1996-1997) Negative biopsies 9/97, 12/97 and 2/98. Excellentquality of life. 6 M/72 Renal carcinoma 10/97 CT initiated and 1-2/daystarting 12/97. Dramatic improvement discontinued due to anuriaFormulation as in example Possible re-start of CT 6 7 F/38 Renalcarcinoma and bone Surgery 2 g/day starting 4/97 Appetite recoverymetastasis 2/98 CT Formulations as in Good tolerance to CT Example 3, 4Good quality of life 8 M/62 Acute myeloblastic CT 3 p/day starting on4/98. Appetite and body-weight leukemia 1/98 Formulations as in exampleback to normal. 6 Cachexia reversion. General improvement.

What is claimed is:
 1. A purified and standardized water-soluble extractobtained from the leaves of Phlebodium decumanum, said extract beingcommonly known as EXPLY-37, having the following characteristics: % byweight Total solid content 79.5-81.5 Ash 10-12 Total N 0.7-0.9 TotalProtein 4.9-5.9 Lipids <0.2 Carbohydrates 60.5-64.5 pH   5-5.1Refractive index 1.4-1.5 UV absorption    235-237 nm    274-284 nmAbsorbance at 290 nm 2.5-5  


2. A method for the preparation of the water-soluble extract accordingto claim 1 comprising the steps of: (a) removing lipid from dry, ground,sporulated Phlebodium decumanum leaves by treatment with petroleumether, methylene chloride or mixtures thereof to yield a delipidatedwater soluble fraction; (b) extracting said water soluble fraction witha mixture of methyl alcohol and water, (c) removing methyl alcohol fromsaid fraction at reduced pressure, (d) purifying the resultant watersoluble fraction by treatment in a mixed ion exchange column containingactive charcoal, sodium metabisulphite and filtration, and (e)concentrating the resultant purified water soluble fraction until abatch-to-batch constant and reproducible extract is obtained.
 3. Amethod for the preparation of the water soluble extract according toclaim 1 comprising the steps of: (a) extracting dry, ground, sporulatedPhlebodium decumanum leaves by treatment with a mixture of methylalcohol and water to yield a water soluble fraction, (b) removing methylalcohol from said fraction at reduced pressure, (c) removing lipids fromsaid fraction with petroleum ether, methylene chloride or mixturesthereof, (d) purifying the delipidized fraction by passing it through amixed ion exchange column including active charcoal and sodiummetabisulphite and filtering the fraction, and (e) concentrating theresultant purified water soluble fraction until a batch-to-batchconstant and reproducible extract is obtained.
 4. A composition obtainedaccording to the method of claim
 2. 5. A composition obtained accordingto the method of claim
 3. 6. A composition prepared according to claim 2comprising from 50-750 mg of the water-soluble extract obtained from theleaves of Phlebodium decumanum in a soft gelatine capsule.
 7. Acomposition prepared according to claim 2 further comprising from 50-750mg of an extract of Phlebodium decumanum rhizome in a soft gelatinecapsule.
 8. The composition according to claim 7 wherein the ratio ofEXPLY-37 to the extract of Phlebodium decumanum rhizome ranges from50:50 to 95:5.
 9. A composition prepared according to claim 2 furthercomprising ground, homogenized extract of Phlebodium decumanum rhizome,said composition being in the form of a dry powder in a hard gelatinecapsule containing from 100-500 mg of said powder.
 10. A compositionaccording to claim 9 wherein the ratio of ground, homogenized Phlebodiumdecumanum rhizome to EXPLY-37 ranges from 4:1 to 1:1.
 11. A compositionprepared according to claim 2 further comprising ground, homogenizedPhlebodium decumanum rhizome and an extract of Phlebodium decumanumrhizome, said composition being in the form of a dry powder in a hardgelatine capsule containing from 100-500 mg of said powder.
 12. Acomposition according to claim 11 wherein the ratio of EXPLY-37 to saidextract of Phlebodium decumanum rhizome ranges from 50:50 to 95:5.
 13. Acomposition according to claim 11 of wherein the ratio of the mixture ofEXPLY-37 and the extract of Phlebodium decumanum rhizome to ground,homogenized Phlebodium decumanum rhizome ranges from 4:1 to 1:1.
 14. Acomposition prepared according to claim 2 further comprising excipientssuitable for liquid preparations.
 15. A composition prepared accordingto claim 2 further comprising a liquid extract of Saccharum officinarum,a liquid extract of Glycyrrhiza glabra, citric acid, inverted sugar,sorbitol, propylene glycol and mixtures thereof, said composition beingin the form of a syrup having a concentration of EXPLY-37 ranging from20-500 mg/ml.
 16. The composition according to claim 14 furthercomprising an extract of Phlebodium decumanum rhizome, said compositionbeing in the form of a syrup having an admixed concentration of EXPLY-37and the extract of Phlebodium decumanum rhizome between 20-500 mg/ml.17. The composition according to claim 16 wherein the ratio of EXPLY-37to the extract of Phlebodium decumanum rhizome ranges from 50:50 to95:5.
 18. A nutritional supplement comprising a composition prepared inaccordance with claim 2.